Radioiodinated quinoline derivatives

ABSTRACT

Radioiodinated analogs of 4-substituted-7-iodoquinolines when administered parenterally or orally are selectively concentrated in animal tissues containing melanin and may be used for the detection and location of melanotic tumors as well as other abnormal growths. The preferred quinoline compounds are 4(dialkylaminoalkylamino)-7-iodoquinolines, such as for example 4(3-dimethylaminopropylamino)-7-iodoquinoline. The radioiodinated compounds are prepared by isotope exchange between the natural iodinated compounds and radioactive alkali metal iodides.

United States Patent 1191 Counsell et al.

[ 1 Apr. 17, 1973 1 RADIOIODINATED QUIINOLINE DERIVATIVES [73] Assignee:The Regents of the University of Michigan, Ann Arbor, Mich.

[22] Filed: May 31, 1968 [2]] App]. No.: 733,248

[52] US. Cl.... .....260/288 A, 260/279 R, 260/288 R, 260/289 R, 424/1,424/258 [58] Field ofSearch..... ..260/288, 288 A, 694; 424/1 [56]References Cited UNITED STATES PATENTS 3,145,197 8/1964 Hoey ..260/5I8A2,554,316 5/1951 Reid ..424/1x 2,911,338 11/1959 Tabem etal... ..424/13,339,072 8/1967 Edwards ....252/301.1x

2,233,970 3/1941 Andersagetal.... ..260/288 3,091,571 1 5/1963 Polinger.424/258 3,406,176 10/1968 Surrey et al. 260/288 X OTHER PUBLICATIONSCounsel] et al., Jour. Pharm. Sci., Vol. 56, p. 1,042-4 1967) PrimaryExaminerDonald G. Daus Attorney-Lawrence S. Levinson, Merle J. Smith,Donald J. Perrella and Burton Rodney 5 7 ABSTRACT Radioiodinated analogsof 4-substituted-7-iodoquinolines when administered parenterally ororally are selectively concentrated in animal tissues containing melaninand may be used for the detection and location of melanotic tumors aswell as other abnormal growths. The preferred quinoline compounds are 4-(dialkylaminoalkylamino)-7-iodoquinolines, such as for example4-(3-dimethylaminopropylamino)-'7- iodoquinoline. The radioiodinatedcompounds are prepared by isotope exchange between the natural iodinatedcompounds and radioactive alkali metal iodides.

5 Claims, No Drawings RADIOIODINATED QUINOLINE DERIVATIVES BACKGROUND OFTHE INVENTION l.-Field of the Invention The present invention relatesbroadly to the field of radioactive compositions and move particularlyto radioiodinated analogs of 7iodoquinolines and to methods of preparingand using such analogs.

2. Description of the Prior Art The use of various compounds labeledwith radioactive elements for diagnosis and radiotherapy of variouspathological conditions, including malignant tumors, is well known.Compounds of this kind which could be used for the early detection andtreatment of melanotic tumors have not heretofore been known, and theuse of certain radioiodinated compounds for this purpose was firstsuggested by the present applicant in the Journal of PharmaceuticalSciences, Volume56, No. 8, pages 1042-4044, Aug., 1967.

It has previously been noted that a number of quinoline, acridine,phenothiazine and other polycyclic drugs and dyes are rapidly absorbedby melanin whereas monocyclic compounds such as pyridine andhydroquinone as well as aliphatic compounds have no such affinity forthe biopolymer.

It has also been noted that certain drugs such as chloroquine andchloropromazine have a marked affinity for pigmented tissue containingmelanin. I While many chloroquinolines have been prepared and tested asantimalarial drugs, few iodinated compounds of this kind have beendescribed. A. R. Surrey and H. F. Hammer (J. Am. Chem. Soc., 68 ll3(1946)) reported the preparation of 4(4-diethylamino-lmethylbutylarnino)-7-iodoquinoline, but did not prepare this compound labeled withradioactive iodine or suggest any utility for such a compound.

SUMMARY OF THE INVENTION derivatives corresponding to theforinula:

enriched in an iodine isotope I is an iodine isotope selected fromiodine-123, iodine-I25, iodine-l3] or iodine-l32; and R is selected fromalkylamino, dialkylamino, dialkylaminoalkylamino, alkoxy, hydroxyalkoxy,or dialkylaminoalkoxy groups and the acid addition I salts thereof. Moreparticularly, the invention relates to compounds corresponding to theformulas:

iodine-123 where n is a number from O. to 5, and I is an iodine isotopeselected from the group consisting of iodine- 123, iodine-125,iodine-131 and iodine-132 and the acid addition salts thereof.

The invention also comprises methods of preparing iodine-containingcompounds of the kind described above which methods comprise reacting4-chloro7- iodoquinoline, in which the iodine is preferably the stablenon-radioactive isotope iodine127, with a compound having the formula RHwhere R is a radical as defined above. This reaction is preferablycarried out by heating the compounds at a temperature sufficient toeffect replacement of the chlorine atom by the radical R-. The resulting4-substituted-7-iodoquinoline is isolated and, if desired, it can bepurified and stored for later use in preparing pharmaceutically usefulradioactive compounds. To prepare such radioactive compounds, the4-substituted-7-iodoquinoline is interacted with a radioactive alkalimetal iodide to effect isotope exchange and so introduce adiagnostically useful proportion of radioactive iodine in the saidquinoline compound. The isotope exchange may, for example, be carriedout by dissolving the 4-substituted-7-iodoquinoline compound and theradioactive metal iodide in a suita v ble solvent and heating thesolution at an'elevated temperature for a length of time sufficient toeffect sub stantial interchange of iodine between the iodoquinolinecompound and the radioactive iodide.

The invention further relates to pharmaceutical compositions comprisinga compound of the kind described.

above in which the iodine is a radioactive isotope, and said compoundbeing dissolved-in a pharmaceutically acceptable solvent. The iodineradioisotope is preferably one having a gamma-radiation energy of notmore than 500 kev. I Y

The invention also relates to a method for detecting and locatingmelanotic tumors in living animals which comprises parenterally ororally administering a detectable dose of a radioactive compound of thekind described above and then subsequently scanning the animal by meansof a conventional radiation scanning device to determine the loci andintensity of radiation mors in living animals comprise administering tothe animal a detectable dose of a compound having quin oline as itsnucleus to which is attached a radioisotope of iodine, the saidradioisotope preferably having a gamma-radiation energy of not more than500 kev., a1- lowing sufficient time for the said compound to beconcentrated in any melanotic tumors present in said animal, and thenscanning the animal by means of a conventional radiation scanning devicefor radioactive loci within the animal.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Among the preferred compoundsof this invention are those in which the organic radical R in the firstformula shown above is an alkylamino or substituted-alkylamino group. Asexamples of such compounds may be mentioned: 7-iodoquinoline compoundsin which the substituent at the 4-position is an alkylamino group suchas dimethylamino, diethylamino, dipropylamino, hexylamino,4-methy1penty1amino, pentylamino, 4- methylbutylamino, butylamino,propylamino, 3- methylpropylamino, etc. Likewise the substituent at the4-position may be a substituted-alkylamino group such as adialkylamino-substituted alkylamino group.

Examples of such substituents are 2- dimethylaminoethylamino, 3-dimethylaminopropylamino, 3- diethylaminopropylamino, 3-

dipropylaminopropylamino, 4-dimethy1aminobutylamino,5-dimethylaminopentylamino, and the like. Such compounds may beprepared, for example, by reacting 4-chloro-7-iodoquinoline with anappropriate amine.

The 4-substituent may also be an alkoxy or substituted alkoxy group.Examples of such groups are ethoxy, hydroxyethoxy, propoxy,3-dimethy1propxy, pentyloxy, 4-dimethylaminopentyloxy, 4-diethylaminopentyloxy, and the like. Such 4-alkoxysubstituted compoundsof the invention may be prepared, for example, by reacting 4-ch1oro-7-iodoquinoline with an appropriate alcohol or alkali metal alkoxide.

For diagnostic purposes radionuclides with a gramma-radiation energy ofless than 500 kev. are preferred. Examples of such isotopes areiodine-125 which has a half-lifeof 60 days and a radiation energy of 35kev. and iodine-131 which has a half-life of 8 days and a radiationenergy of'360 kev. While the synthesis and storage of compoundscontaining iodine-125 is simpler, for some purposes the higher radiationenergy of iodine-131 may be necessary or desirable. Other knownradioisotopes of iodine, such as iodine-123 and iodine-132, are alsouseful and may even be advantageous for certain purposes.

The compounds of the present invention are preferably used in the formof one of their water-soluble acid addition salts. Methods for preparingsuch salts are well known to those skilled in the art. In practice,saltswith hydrochloric acid have been found to be very satisfactory andare usually preferred, but the acid addition salts of other strongmineral acids such as hydrobromic acid, nitric acid, sulfuric acid, orstrong organic acids such as glacial acetic acid are also useful.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of 4-(3-Dimethylaminopropylamino)-7- iodoquinolineA solution of 4-ch1oro'7-iodoquinoline (2.5 g.) in 3-dimethyaminopropylamine (10 ml.) was heated at the reflux temperaturefor up to 23 hrs. The excess amine was removed by distillation underreduced pressure and the residual oil dissolved in a minimum of acetone.NH OH was added and the resulting yellow precipitate was collected byfiltration and washed with water. Several .recrystallizations fromacetone afforded pale yellow needles (2 g., 65 percent) of the desiredproduct, mp 101-103, nmr peaks at 7.64 (NCH 7.43 (CH N), (triplet, J 6cps.) and 6.67 ppm (CH NH, multiplet). The latter became a triplet upondeuteration (J 6 cps.) The IR spectra was as expected. Anal. (C H INcalcd. C 43.21, H 4.14; found C 43.34, H 4.11. Acute toxicity tests inmice gave an LD value of 58 mg./kg. with confidence limits of 49.6 to67.9 mg./1 g.

EXAMPLE 2 Preparation of 4-(4-Methy1pentylamino)-7-iodoquinoline Asolution of 4-ch1oro-7-iodo'quino1ine (2 g.) in 4- methylpentylamine (4ml.) was heated under reflux for 23 hrs. and the excess of solventevaporated under reduced pressure. Addition of acetone to the residuegave a solid hydrochloride (1.75 g.), mp 168173 and V 2,700 cm (NW-I).Recrystallization from EtOHMe CO gave an analytical sample, mp 183-4.The motor liquors afforded a second fraction (0.35 g.), mp 130-135,which upon recystallization from ethyl alcohol-water gave the desiredbase in pure form, mp 1445. Treatment of an ethyl alcohol solution ofthe HCl salt gave the same free base. Anal. (C H IN Ca1c.C 50.88, H5.41; found C 50.74, H 5.32. The IR and nmr spectra were as expected. 7

EXAMPLE 3 Preparation of iodoquinoline A mixture of3-dimethylamino-l-propanol (1.45 g., 0014M) and sodamide (0.67 g.,0.017M) in dry toluene 15 ml.) was heated under reflux until theevolution of ammonia ceased (about 3 hrs.). The grey suspension wascooled and a solution of 4-chloro-7- iodoquinoline (1 g., 0.0034M) intoluene (5 m1.) added dropwise with stirring. The reaction mixture washeated under reflux for 18 hrs. On cooling, water was added to dissolvethe solid material, and the toluene phase was separated, dried oversodium sulfate, and evaporated to leave a pale brown oil whichsolidified upon addition of petroleum ether (bp, 30-40). The white solid(0.7 g., 57 percent) mp 90, was recrystallized from acetone to give ananalytical sample, mp 934, V,,,,,,1180 cm- (COC), and nmr peaks at 2.29(NMe 2.50 (triplet, J 6 cps., NCH' and 4.23 ppm (triplet, J 6 cps., -OCHAnal. (C H IN O) Calcd. C 47.22, H 4.81; found C 47.37, H 4.80.

4-(3-Dimethylaminopropoxy)-7- EXAMPLE 4.

Preparation of 4-(4-Methylpentyloxy)-7-i0doquino1ine 'A solution of4-chloro-7-iodoquinoline (3.1 g.) in toluene (5 ml.) was added dropwisewith stirring to a previously heated mixture of 4-methyl-l-pentanol (4.4g.) and sodamide (2.1 g.) in toluene ml). The reacdescribed in Example4, the solvent was removed in vacuo, the residue treated with watercontaining a little acetone, and the precipitate collected. In allcases, the products were purified by recrystallization and the putionwas carried out as in Example 3 and afforded a -rity established by (a)TLC and a radiochromatogram white solid (2.45 g.)-, mp 8588.Recrystallization of .the strip and b) admixture melting point with fromhexane gave the desired compound in pure form, authentic samples.Further details of the individual mp 97-9, V at 1,115 cm" (CO-C) and nmrpreparations are given in Table l.

TABLE I Percent Bath Reaction Rccrystalliza- Spec. act Compound Solventtemp. time (hr.) tionsolvunt Recovery Exchange (L/mg Examplol A 170-5 10MezCO-HzU 53 50.0 5.00 Example 2.-

11 1005 48 EtOlI-lIzO 15 40 14.5 Example 3. 0 205-10 24 MczCO-HaO 55 2.50.51 Examplo D 175-150 48 EtOHHz0 7 4.8 1. 44

l A=ethylcno glycol, 13 =pivallc acid, C =3-dimethylamino-l-propan0l,D=4-methyl-1-pentan0l.

peaks at 9.94 [doublet, J 6 cps, C-(Cl-l and 4.15 ppm. (triplet, J 6.5cps, -OCH Anal. (C H l NO) Calcd. C 50.72, H 5.1 l;found C 50.80, H4.98.

EXAMPLE 5 Preparation of 4-Dimethylamino-7-iodoquinoline Dimethylaminegas was bubbled through an icecooled solution of4-chloro-7-iodoquinoline (2 g.) in

toluene ml.) and methylethyl ketone (10 ml.) for 3 hours in a pressurebottle. The bottle was tightly stoppered and placed in an oven at 50C.for 10 days. The

- mixture was cooled and washed with water. The organic phase was driedover sodium sulfate and the solvent removed in vacuo. Recrystallizationof the solid residue gave the desired compound in pure form (1.1 g.) mpl078, and an nmr peak at 2.99 ppm.

-(NCl-l Anal. c n m Calcd. c 44.32, H 3.72; foundC44.42,H3.59.

EXAMPLE 6 Preparation of 4-Hydroxyethoxy-7-iodoquinoline A solution ofthe compound described in Example 5 (100 mg.) in ethylene glycol (1.5ml.) was heated in an oil bath at 185.for 16 hours, cooled, and dilutedwith water. The precipitate (70 mg.), mp l53-5, was

' recrystallized from acetone-water to give the desired product in pureform, mp 1545. The IR and nmr spectra were as expected. Anal. (C H lNOCalcd. C 41.94, H 3.20; found C 42.03, H 3.25.

EXAMPLE 7 Preparation of Iodine-125 Analogs by Isotope for the specifiedtime and allowed to cool. in the case of the compounds described inExamples 1 and 3, water was added and the product collected byfiltration and washed well with water. For the compound described inExample 2, the solution was concentrated to approximately 0.5 ml. underreduced pressure, treated with water and ammonium hydroxide, and theprecipitate collected as above. For the compound EXAMPLE 8 4 to5-week-old male, black mice of the BL6J strain were injectedintraperitoneally with 10 microcuries of4-(3-dimethylaminopropylamino)7-iodoquinoline containing iodine-125. Theanimals were sacrificed at 12, 24 and 48 hrs. Control mice were injectedvia the same route with 10 microcuries of sodium iodide-125 andsacrificed at the same time intervals. Counting was done in a commercialwell counter. This radioiodinated quinoline compound showed the samemarked affinity for melanin and slow release from pigmented tissues thathad earlier been observed in rats and mice using chloroquine labeledwith carbon-l4. Moreover, the low thyroid activity observed for theanimals receiving the radioiodinated quinoline compound versus thosegiven the sodium radioiodide, indicates that significant diodination didnot occur.

EXAMPLE 9 4-(3-Dimethylaminopropylamino)-7-iodoquinoline containingiodine-125 was injected into Syrian hamsters with malignant melanomas ata dosage of microcuries per animal. Excellentvisualization of themelanotic tumor was obtained within 4 days. The concentration of iodine-111 the tumor was approximate ly 10 times its concentration in othertissues. lts concentration in the melanoma remained constant orincreased for about 5 days following the injection while concentrationsin all other tissues fell rapidly during the first 3 days. There was noevidence of uptake by the thyroid. Since a portion of the injectedmaterial is excreted in the bile, the scans were also made several (35)days after the injection to allow time for the material to be eliminatedfrom the bowels,'spleen and liver.

EXAMPLE 10 When 1 millicurie of 4 (3-dimethylaminopropylamino)-7-iodoquinoline containing iodine-125 wasinjected into a melanotic dog weighing lbs., concentration of theradioactive compound in the melanoma was similar to that observed in theSyrian hamsters described in Example 9.

From the preceding it is evident that the usefulness of the compounds ofthis invention resides in their selective concentration in melanotictissues. It should also be noted that the utility of these compounds isnot necessarily limited to the detection of melanomas, for

- nary sense are of minor significance compared with radiation dosagesand toxicity.

In view of the above, it will be seen that the several objects ofthe-invention are achieved and other advantageous results attained.

As, various changes could be made in the above methods and productswithout departing from the scope of the invention, it is intended thatall matter contained in the above description or shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

What is claimed is:

l. A compound having the formula:

enriched in an iodine isotope selected from the group consisting ofiodine-l23, iodine-125, iodine-131 and iodine 132;

R is selected from the group consisting of H and alkyl having 1 to 6carbons;

R is selected from the group consisting of alkyl having 1 to 6 carbonsand dialkylamino-substituted alkyl having 1 to 6 carbons in each of thealkyls of the dialkyl group and 2 to 5 carbons in the other alkyl group,and the pharmaceutically acceptable acid addition salts thereof.

2; A compound. having the formula:

where n is a number'from 1 to 5, and l is an iodine isotope selectedfrom the group consisting of iodine- 123, iodine-125, iodine-131 andiodine-132, and the pharmaceutically acceptable acid addition saltsthereof.

3. A compound according to claim 2 in which n is 3.

4. A compound according to claim l'in which R is hydrogen and R is theradical 4-methylpentyl.

5. A compound according to claim 1 in which both R, and R are methylradicals.

2. A compound having the formula:
 3. A compound according to claim 2 inwhich n is
 3. 4. A compound according to claim 1 in which R1 is hydrogenand R2 is the radical 4-methylpentyl.
 5. A compound according to claim 1in which both R1 and R2 are methyl radicals.